Stem cells can be viewed as having therapeutic potential either when delivered exogenously or when endogenous cells respond to injury. The central premise of this proposal is that successful therapeutic effect of either is dependent upon the interaction of the stem cells with a complex microenvironment. The regulatory components of this microenvironment function as an integrated system, providing a niche that modulates stem cell fate in response to physiologic stimuli. Yet this aspect of cell based therapy is often ignored. We have previously shown that understanding some components of the hematopoietic stem cell niche {the osteoblast and its response to hormonal stimulation) can lead to a strategy for improving stem cell outcomes in a physiologically meaningful context (parathyroid hormone stimulation to improve bone marrow transplantation). These studies in mice provided proof of principle that understanding and manipulating the stem cell niche can result in a therapeutic result relevant to human disease. Our intent here is to extend this novel, cell based approach to therapy development along two lines. First, to deepen understanding of the components of the hematopoietic stem cell niche and assess how these components function in vivo. Second, to convert this understanding derived from mouse models to clinical trials in humans with hematologic disease. Our program is therefore composed of four main projects, two laboratory based and two clinically based. The main thrust of these is: Project 1: define Wnt signaling effects on osteoblast biology led by Dr. Henry Kronenberg;Project 2: determine the impact of multiple constituents of the bone marrow niche on stem cell function led by Dr. David Scadden;Project 3: convert murine models to human use through chimeric animal studies, engagement of cell manipulation and clinical trial teams for two specific niche-related trials led by Dr. Gregor Adams;Project 4: test manipulation of the niche as a strategy to improve stem cell harvesting or stem cell engraftment in three clinical trials using a clinical trial consortium led by Dr. Karen Ballen. These will be supported by three cores. Success of the proposal will provide rationale for continued development of a novel, niche-based approach to cell therapies for multiple disease entities. Further, it will create infrastructure needed to rapidly move such therapies from mouse model to pre-clinical assessment to human clinical trial.